title: Critical telomere shortening regulated by the ataxia-telangiectasia gene acts as a DNA damage signal leading to activation of p53 protein and limited life-span of human diploid fibroblasts. A review.
abstract: Somatic cells undergo a limited number of doublings in culture and enter an irreversible block in the G1 and G2/M phase of the cell cycle termed "senescence". Telomere shortening presumably as a consequence of the end-replication problem has been proposed to act as a mitotic clock eventually leading to cellular senescence. Several models have been proposed to explain how telomere shortening can lead to cellular senescence. We proposed previously that telomere shortening may eventually lead to formation of dicentric chromosomes which on subsequent breakage activate a DNA damage response pathway involving the p53 protein. Hence we proposed that the telomere shortening signal is perceived by the cell as DNA damage. Recently we have obtained experimental evidence that the p53 protein is activated posttranslationally in human fibroblasts which undergo telomere shortening and subsequent senescence in culture. In this paper we also show that the increased activity of p53 protein coincides with formation of dicentric chromosomes and senescence. Also, we have previously found that an increase in the level of the down stream target of p53 protein, p21WAF1/SD11/C1P1, is dependent on both p53 and p300 proteins. We have also shown that fibroblasts obtained from individuals with Ataxia Telangiectasia lose telomeric DNA at an accelerated rate, activate p53 protein, and undergo premature senescence in culture. These results suggest that the ataxia-telangiectasia gene (ATM) and p53 are involved in surveillance and regulation of telomeric DNA. Once a critical length of telomeric DNA is reached. ATM and p53 sense and relay this signal to the cell cycle leading to senescence.
authors.affiliation: Ontario Cancer Institute, Toronto, Canada. Vaziri@oci.utoronto.ca
authors.forename: H
authors.initials: H
authors.lastname: Vaziri
mesh_terms: D001260:Ataxia Telangiectasia / Q000235:genetics*; D002453:Cell Cycle; D002461:Cell Line, Transformed; D016922:Cellular Senescence / Q000502:physiology*; D004249:DNA Damage; D004171:Diploidy; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D006801:Humans; D008938:Mitosis; D015398:Signal Transduction; D016615:Telomere / Q000235:genetics / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53